title: Effect of PF-04217329 a prodrug of a selective prostaglandin EP(2) agonist on intraocular pressure in preclinical models of glaucoma.
abstract: Better control of intraocular pressure (IOP) is the most effective way to preserve visual field function in glaucomatous patients. While prostaglandin FP analogs are leading the therapeutic intervention for glaucoma, new target classes also are being identified with new lead compounds being developed for IOP reduction. One target class currently being investigated includes the prostaglandin EP receptor agonists. Recently PF-04217329 (Taprenepag isopropyl), a prodrug of CP-544326 (active acid metabolite), a potent and selective EP(2) receptor agonist, was successfully evaluated for its ocular hypotensive activity in a clinical study involving patients with primary open angle glaucoma. In the current manuscript, the preclinical attributes of CP-544326 and PF-0421329 have been described. CP-544326 was found to be a potent and selective EP(2) agonist (IC(50) = 10 nM; EC(50) = 2.8 nM) whose corneal permeability and ocular bioavailability were significantly increased when the compound was dosed as the isopropyl ester prodrug, PF-04217329. Topical ocular dosing of PF-04217329 was well tolerated in preclinical species and caused an elevation of cAMP in aqueous humor/iris-ciliary body indicative of in vivo EP(2) target receptor activation. Topical ocular dosing of PF-04217329 resulted in ocular exposure of CP-544326 at levels greater than the EC(50) for the EP(2) receptor. PF-04217329 when dosed once daily caused between 30 and 50% IOP reduction in single day studies in normotensive Dutch-belted rabbits, normotensive dogs, and laser-induced ocular hypertensive cynomolgus monkeys and 20-40% IOP reduction in multiple day studies compared to vehicle-dosed eyes. IOP reduction was sustained from 6 h through 24 h following a single topical dose. In conclusion, preclinical data generated thus far appear to support the clinical development of PF-04217329 as a novel compound for the treatment of glaucoma.
authors.affiliation: Department of Ocular Biology, Pfizer Global R & D, San Diego, CA 92121, USA. gprasann@hotmail.com
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
authors.forename: Samantha
authors.initials: S
authors.lastname: Carreiro
authors.forename: Scott
authors.initials: S
authors.lastname: Anderson
authors.forename: Hovhannes
authors.initials: H
authors.lastname: Gukasyan
authors.forename: Soisurin
authors.initials: S
authors.lastname: Sartnurak
authors.forename: Husam
authors.initials: H
authors.lastname: Younis
authors.forename: David
authors.initials: D
authors.lastname: Gale
authors.forename: Cathie
authors.initials: C
authors.lastname: Xiang
authors.forename: Peter
authors.initials: P
authors.lastname: Wells
authors.forename: Dac
authors.initials: D
authors.lastname: Dinh
authors.forename: Chau
authors.initials: C
authors.lastname: Almaden
authors.forename: Jay
authors.initials: J
authors.lastname: Fortner
authors.forename: Carol
authors.initials: C
authors.lastname: Toris
authors.forename: Michael
authors.initials: M
authors.lastname: Niesman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lafontaine
authors.forename: Achim
authors.initials: A
authors.lastname: Krauss
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D000287:Administration, Topical; D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002924:Ciliary Body / Q000378:metabolism; D003315:Cornea / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D005902:Glaucoma, Open-Angle / Q000188:drug therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D007498:Iris / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D009883:Ophthalmic Solutions / Q000493:pharmacokinetics / Q000494:pharmacology; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists* / Q000378:metabolism; D013449:Sulfonamides / Q000493:pharmacokinetics / Q000494:pharmacology*; D014065:Tonometry, Ocular
chemical_list: D000085:Acetates; D000959:Antihypertensive Agents; C568860:CP 544326; D009883:Ophthalmic Solutions; C568861:PF 04217329; D011355:Prodrugs; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013449:Sulfonamides; D000242:Cyclic AMP; D002118:Calcium